Bronchial asthma is a complex multifactorial disease characterized by hyperactivity of the respiratory tract to external stimuli. Airway inflammation leads to a number of severe lung diseases including Asthma and chronic obstructive pulmonary diseases (COPD also known as Chronic Obstructive Airway Disease, Chronic Obstructive lung Disease or chronic airflow limitation and chronic airflow obstruction). The airflow limitation is usually progressive and associated with abnormal inflammatory response of the lungs to noxious particles or gases.
Many biological responses are mediated by levels of cyclic nucleotides mainly cAMP and cGMP which in turn are synthesized by adenylyl cyclases (ACs) and guanylate cyclases (GCs). To regulate levels of cAMP and cGMP, all cells have Phosphodiesterases (PDEs) that hydrolyze cAMP and cGMP to 5′-AMP and 5′-GMP. In humans there are 21 different PDE isoforms that are classified into 11 different groups. Basically these PDEs fall into three categories: 1. those that are specific to cAMP, 2. Those that are specific to cGMP and 3 those that act on both cAMP and cGMP. These 11 groups of PDEs are classified according to their nucleotide selectivity. PDE4 has 4 isoforms and in all the isoforms upstream conserved regions (UCRs) are present which appear to modulate dimerisation and may bind to signaling molecules such as lipids. There are at least 18 different splice variants of the four PDE4 isoforms. Because of the critical role of cAMP in mediating cytokine responses cAMP PDEs are also implicated. Many of the mediators of inflammatory response such as T cells, B cells, monocytes, neutrophils, eosinophils and macrophages have PDE4 enzymes as their primary cAMP PDE. Among the inflammatory diseases that are implicated by these cellular mediators are asthma, chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, inflammatory bowel disease, crohn's disease and multiple sclerosis. Consequently the development of PDE4 inhibitors as therapeutic agents for these diseases has been a major pharmaceutical focus. PDE4 indirectly controls the degree of bronchodilation. In the inflammatory cells cAMP is a negative regulator of the primary activating pathways such as cytokine release by T-cells. Inhibition of the PDE4 isozymes in these cells results in elevated cAMP levels and consequent inactivation of the inflammatory response. In addition to the direct role of cAMP in inflammatory cell function, elevated cAMP levels also lead to smooth muscle relaxation. Consequently, inhibition of PDE4 activity leading to higher cAMP levels cause bronchodilation thereby alleviating symptoms of respiratory diseases such as asthma or COPD.
Also Inhibition of PDE-IV enzyme increase levels of cAMP and Cyclic AMP modulates the activity of the most of the cells that contribute to the pathophysiology of allergic asthma. Elevation of cAMP would produce beneficial effects, some of which includes apart from airway smooth muscle relaxation, inhibition of mast cell mediator release, suppression of neutrophil degranulation, inhibition of basophil degranulation and inhibition of monocyte and macrophage activation. The connection between PDE4 activity and cognition has been speculated ever since the discovery that the cAMP-regulating dunce gene of the fruit fly encodes a PDE4 homologue (Nature, 1981, 289, 5793, 79-1; J. mol. biol., 1991, 222, 3, 553-565). Another two important roles for PDE4D have recently been identified in cardiovascular tissue; one is a correlation for PDE4 polymorphism with stroke and another is an involvement in vascular smooth muscle cell proliferation (Mol. Pharmacol. 2005, 68, 3, 596-605). Finally, there are reports linking between PDE4D and osteoporosis. Specifically single nucleotide polymorphisms mapping to the PDE4D gene are linked to variability in bone mineral density (BMC Med. Genet, 2005, 6, 1, 9).
Inflammatory leukocytes infiltrate the airways of asthmatic patients in which eosinophils are the major component and also they are accumulated more in the lungs. When activated they synthesize and release inflammatory cytokines such as Interleukine-1, Interleukine-2 and Tumor Necrosis Factor-α (TNF-α) as well as inflammatory mediators. Thus, the compounds of the present invention also inhibit the production of Tumor Necrosis Factor, a serum glycoprotein, which is involved in the pathogenesis of a number of autoimmune and inflammatory diseases. TNF-α production in pro-inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3′5′-monophosphate (cAMP) which in turn is regulated by PDE family of enzymes.
Nonselective PDE inhibitors like theophylline have been used for the treatment of bronchial asthma and the side effects of which include cardiac dysarhythmias and nausea which are believed to be the results of non selectivity among PDEs Of the 11 known isozymes of the PDE family, PDE4 appears to be the predominant in various inflammatory cells and hence the current research on selective PDE4 inhibitors.
First generation PDE4 inhibitors include Rolipram and Ro20-1724 which belong to the catechol diether group. Because of side effects like nausea, vomiting and increased gastric acid secretion their development as therapeutics has been halted.

Current drug discovery efforts involved the design of the PDE4 inhibitors with reduced side effects while maintaining the anti inflammatory properties of rolipram. Compound like Cilomilast, roflumilast, Lirimilast and AWD-12-281 belong to the second generation PDE4 inhibitors. A few showed less side effects and roflumilast and cilomilast have progressed to the advanced stages of development.

PDE4 inhibitors can be divided into distinct classes based on structural motifs present in the molecules for e.g. Xanthine, nitraquazone, catechol diethers etc. Examples of which are theophylline, arofylline, nitraquazone, almirall, piclaminast, and filaminast, respectively. Several compounds have been developed as PDE4 inhibitors that do not fall into any one particular class of compounds like Lirimilast (BAY-19-8004), a novel sulfinate containing compound for the treatment of COPD. Tofimilast from Pfizer is an indazole derivative which is currently under clinical development. The development of ibudilast, a pyrazolopyridine compound, as a vasodilator and for the treatment of allergic ophthalmic disease is in highest phase and for multiple sclerosis it is in phase II trials. BAY-61-9987 belongs to imidazotriazinones under development by Bayer for the potential treatment of respiratory diseases (GB2388594A1-2003).
PDE4 inhibitors have been shown to relax airway smooth muscle and to suppress the activation of inflammatory cells. PDE4 inhibitors that are at various stages of clinical development are cilomilast, roflumilast, AWD-12-281,CC-10004,ONO-6126 and GRC-3886. GRC3886 inhibits PDE4 isozyme subtypes A,B,C and D. It has a good oral bioavailability across various animal species and no emetic effect had been noted at oral dosages of up to 100 mg/kg. The drug was safe, well tolerated and has excellent pharmacokinetics with a long half-life.
Patent application WO 93/19749 claims the compounds of formula I which are useful for allergy and inflammatory states.

Where X4 is
One of the representative examples of this patent is as given below.

U.S. Pat. No. 5,712,298 claims the compounds of formula I which is a phosphodiesterase inhibitor for treating airway disorder and dermatitis.
in which
R1 is 1-4C-alkoxy which is completely or partially substituted by fluorine,
R2 is 3-5C-cycloalkylmethoxy or benzyloxy and
R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethyoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3-5-dibromopyrid-2-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl, a salt thereof, and the N-oxide of a pyridine or a salt thereof.
The claimed compounds include
U.S. Pat. No. 5,811,455 claims the compounds of formulae I and II
One of the representative examples of this invention is
International patent application WO 2006/011024 claims the compounds of generic formula

One of the representative compounds is as given below and the application claims their use in the treatment of asthma and chronic obstructive pulmonary disease apart from other disease states.

Challenges that are facing the PDE4 inhibitors are mainly nausea, vomiting, increased gastric acid secretion which may be because of selectivity towards binding sites. Based on the prior art reports compounds with selectivity for the high-affinity rolipram binding site causes side effects where as compounds with selectivity for low-affinity rolipram binding site are expected to have better therapeutic effects compared to rolipram (J. Biol. Chem. 1992, 267(3):1798-1804; J. Biol. Chem. 1999, 274(17):11796-11810). Other side effects are cardiac dysarhythmias, vasculitis and osteoporosis.
PDE10 sequences were first identified by using bioinformatics and sequence information from other PDE gene families. Homology screening of EST databases revealed PDE10A as the first member of the PDE10 family of phosphodiesterases. PDE10A has been shown by localization studies to have the most restricted distribution of all the 11 known PDE families, with the PDE10A mRNA highly expressed only in the brain and testes (J. Biol. Chem. (1999)274:18438-18445; Eur. J. Biochem (1999)266:1118-1127). This unique distribution of PDE10A in the brain indicates a potential use of PDE10A inhibitors for treating neurological and psychiatric disorders. However, PDE10A inhibitors have also been claimed to be useful as treatment for cancer, diabetes and especially obesity.
PDE10A like all PDEs has a conserved segment of ˜270 amino acids in the C-terminal end and this segment has been demonstrated to include the catalytic site. The human PDE10 gene is large, over 200 kb, with up to 24 exons coding for each of the splice variants. The amino acid sequence is characterized by two GAF domains (which bind cGMP), a catalytic region and alternatively spliced N and C termini. Numerous splice variants are possible because of at least 3 alternative exons encoding the N and 2 for the C-termini. PDE10A1, a splice variant of PDE10, is a 779 amino acid protein that hydrolyses cAMP and cGMP. The Km values for cAMP and cGMP are 0.05 and 3.0 micro molar respectively. PDE10 is a unique cAMP-inhibited cGMPase (J. Biol. Chem. (1999)274:18438-18445).
PDE10A has been identified in the islets of Langerhans. PDE10A hydrolyses cAMP to AMP and thereby decreases intracellular concentrations of cAMP. By inhibiting PDE10A activity, intracellular levels of cAMP are increased thereby the release of insulin-containing secretory granules and therefore, increasing insulin secretion.
PDE10A inhibitors are known to play a role in treating cardiovascular disorders such as hypertension, ischemic heart disease, myocardial infarction and ischemic stroke. Expression of PDE10 can be detected in the heart (Gene 234:109-117, 1999; Biochem. Biophy. Res. Comm, 261:551-557, 1999), and cGMP and cAMP are important second messengers that are involved in the regulation of vascular smooth muscle tone. The PDE10 family comprises enzymes that are responsible for the degradation of cAMP and cGMP in various tissues and the activation of soluble and membrane bound guanylate cyclases leads to increased intracellular cGMP levels and induces vasodilation. The stimulation of various GPCRs (G-protein coupled receptors) which are expressed in vascular smooth muscle cells induces the activation of adenylate cyclases, generation of intracellular cAMP, and produces vasodilation. Thus PDE10A likely plays a role in the cardiovascular system.
PCT application WO 2005/012485 by Bayer claims the use of PDE10 inhibitors for the treatment of diabetes and the compounds disclosed are

European patent application EP 1 250 923 by Pfizer broadly claims the use of selective PDE10 inhibitors for the treatment of CNS disorders exemplified by psychosis and disorders comprising deficient cognition as symptom. The only PDE10 inhibitor exemplified in this patent is papaverine and it discloses IC50 values of papaverine for all PDE families.
PCT application WO 2004/002484 by Kyowa Hakko kogyo Co., claims the compounds of following formula as PDE10 inhibitors.

PDE10A is emerging as a particularly interest target for CNS disorders. This is due to the very restricted localization of PDE10A in key brain areas. Inhibition of PDE10A using the relatively specific PDE10A inhibitor, papaverine shows a reduction in activity and a reduced response to psychomotor stimulants. Inhibition also reduces the conditioned avoidance response predictive of clinical antipsychotic activity. PDE10 inhibitors are also shown to be potential targets in treating Diabetes and complications thereof and only a few prior art references (WO 2002/048144, WO 2003/014117, WO 2003/014116, WO 2003/014115, WO 2003/051877) by Bayer pharmaceuticals show that PDE10 inhibitors play a role in treating cancer. Due to the various roles that PDE10 inhibitors show, they have become the most promising targets for future drug therapies for different therapeutic areas.
As described above, as regulation of intracellular signaling is coordinated by PDE4, it has become a validated target for the development of therapeutics for inflammatory diseases such as asthma and COPD. PDE4 also has shown to be a potential target for CNS related diseases, depression, memory enhancement, cardiovascular disease and osteogenesis.